Methods for the treatment of rosacea

ABSTRACT

The present invention relates to pharmaceutical compositions for topical use (including also dermatological compositions), for treating skin conditions and afflictions, such as rosacea and symptoms and conditions associated there from.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation application from U.S. applicationSer. No. 15/879,600, filed Jan. 25, 2018; which is a Continuationapplication from U.S. application Ser. No. 15/496,344, filed Apr. 25,2017; which is a Continuation application of U.S. application Ser. No.13/686,533, filed Nov. 27, 2012, now U.S. Pat. No. 9,687,465, grantedJun. 27, 2017; which are all incorporated in their entirety herein byreference.

TECHNOLOGICAL FIELD

This invention relates to pharmaceutical compositions for topical use(including also dermatological compositions), for treating skinconditions and afflictions, such as rosacea and symptoms and conditionsassociated there from.

BACKGROUND

Rosacea is a chronic disease of inflammatory dermatitis that mainlyaffects the median part of the face and the eyelids of certain adults.It is characterized by telangiectatic erythema, dryness of the skin,papules and pustules. Conventionally, rosacea develops in adults fromthe ages of 30 to 50; it more frequently affects women, although thecondition is generally more severe in men. Rosacea is a primitivelyvascular condition whose inflammatory stage lacks the cysts andcomedones characteristic of common acne.

Factors that have been described as possibly contributing towards thedevelopment of rosacea include for example: the presence of parasitessuch as the Demodex folliculorum, the presence of bacteria such asHelicobacter pylori (a bacterium associated with gastrointestinaldisorders), hormonal factors (such as endocrine factors), climatic andimmunological factors, and so forth.

Rosacea develops in four stages over several years, in spasms aggravatedby variations in temperature, alcohol, spices, exposure to sunlight andstress.

The various stages of the disease are the following:

Stage 1: stage of erythema episodes. The patients have erythrosis spasmsdue to the sudden dilation of the arterioles of the face, which thentake on a congestive, red appearance. These spasms are caused by theemotions, meals and temperature changes.

Stage 2: stage of couperosis, i.e., of permanent erythema withtelangiectasia. Certain patients also have oedema on the cheeks and theforehead.

Stage 3: inflammatory stage (papularpostular rosacea) with appearance ofinflammatory papules and pustules, but without affecting the sebaceousfollicles and thus with absence of cysts and comedones.

Stage 4: rhinophyma stage. This late phase essentially affects men. Thepatients have a bumpy, voluminous red nose with sebaceous hyperplasiaand fibrous reordering of the connective tissue.

Typical treatment of rosacea include oral or topical administration ofantibiotics such as tetracyclines, salicylic acid, anti-fungal agents,steroids, metronidazole (an anti-bacterial agent) or with isotretinoinin severe cases, or even with anti-infectious agents such as azelaicacid.

US 20110052515 described a pharmaceutical/dermatological topicallyapplicable formulation for treating rosacea, comprising at least oneavermectin compound and benzoyl peroxide (BPO, an anti-acne agent).

Breneman et al. (Int. J. Derma. 43, 381-387 (2004)) reported the resultsof a double blind randomized vehicle-controlled clinical trial ofonce-daily BPO and clindamycin topical gel in the treatment of moderateto severe rosacea.

Montes et al. (Cutis, 32, 185-190 (1983)) disclosed the use of BPOdissolved in acetone gel formulation for the treatment of rosacea.

Wester et al. (J. Am. Acad. Derma. 24, 720-726 (1991)) related to thecontrolled release of BPO from porous microsphere polymeric systems inthe treatment of acne.

These previous rosacea treatments with BPO alone or in combination withother agents, have been shown to have severe drawbacks such asirritation and intolerance phenomena, especially when they areadministered for a prolonged period. On the other hand, these treatmentsare only suppressive and not curative, acting especially on thepustulous spasms occurring during the inflammatory stage.

Considering the chronic nature of rosacea, there is a need for aprolonged use treatment of the disease, its symptoms and associatedconditions, in a safe and effective manner. Thus, there exists a needfor compositions that show improved efficacy in the treatment ofrosacea, that impart greater tolerance to the active principles and thatdo not have the side effects described in the prior art.

GENERAL DESCRIPTION

Accordingly, the present invention provides a composition comprisingbenzoyl peroxide for topical use in the treatment of rosacea, whereinsaid benzoyl peroxide is in a solid form.

In some embodiments said BPO comprises between about 2.5 weight % toabout 5 weight % of the composition. In some embodiments the BPO is thesingle pharmaceutical active agent in the composition. In otherembodiments the composition further comprises a further active agent(pharmaceutical active agent or a cosmetically active agent).

The term “topical use” is meant to encompass the topical administrationof a composition of the invention by formulating said composition in anyway known in the art, or in formulations disclosed herein, which arecompatible with the skin, mucous membranes and/or the integuments.

The invention further provides a composition comprising benzoyl peroxidefor topical use in the treatment of rosacea, wherein the dissolutionrate of the benzoyl peroxide from composition is less than about 80%weight/h. In some embodiments of this aspect, said benzoyl peroxide isthe single pharmaceutical active agent in said composition.

In some embodiments, said dissolution rate is between about 20% weight/hto about 80% weight/h. In other embodiments, said dissolution rate isbetween about 40 to 60% weight/h. In yet other embodiments, saiddissolution rate is less than about 40% weight/h. In further embodimentssaid dissolution rate is less than about 20% weight/h. In some furtherembodiments said dissolution rate is between about 10% weight/h to about50 weight %/h (i.e. 10, 15, 20, 25, 30, 35, 40, 45, 50%/h).

In the context of the present invention the term “dissolution rate”relates to the rate in weight per time units of dissolution of solid BPOfrom the composition of the invention to the surrounding immediateenvironment. The dissolution rate as disclosed in the presentapplication is measured as disclosed in Example 5 below.

The invention further provides a composition comprising benzoyl peroxidefor topical use in the treatment of rosacea, wherein the dissolutionrate of the benzoyl peroxide from composition is less than about 40mg/h.

It has been found by the inventors of the present application that acomposition comprising BPO, having dissolution rate of less than about80%/h provides a safer and more effective treatment of rosacea withrespect to the tolerance and adverse effect as compared withcompositions having similar amount of pharmaceutical active agent withfaster dissolution. It was shown by the inventors of the applicationthat as the dissolution rate of BPO is lowered to less than 80%/h thetreatment of a chronic skin disease such as rosacea, including itssymptoms and conditions associated therewith, was dramatically improvedsince the controlled release of the pharmaceutical active agent was slowenough to allow for controlled and slow release of the pharmaceuticalactive agent over a prolonged period of time, releasing an amount of BPOable to treat the disease, symptoms and/or conditions associated withrosacea, but on the other hand not allowing for intolerance or adverseeffects to appear. In some embodiments when the composition comprisesBPO as a single pharmaceutical active agent, treatment results ofrosacea were comparable to the compositions know in the art comprisingBPO and an antibacterial agent.

The present invention discloses pharmaceutical compositions, includingdermatological compositions, comprising benzoyl peroxide as a singlepharmaceutical active agent in the solid form. In some embodiments saidcompositions are formulated into a physiologically acceptable form.

In further embodiments a composition of the invention may comprise atleast one further pharmaceutical active agent (in addition to the BPO).

In some embodiments a composition of the invention comprises at leastone further pharmaceutical active agent selected from the groupconsisting of an antibiotic agent, a tetracycline agent, a retinoid, anantimicrobial agent and any combinations thereof.

In some embodiments said at least one further pharmaceutical activeagent is selected from the following non-limiting list: Antibiotics suchas clindamycin or erythromycin. Tetracyclines such as minocycline ordoxycycline. Retinoids and other compounds that bind to and activatesthe RAR and/or RXR receptors such as all trans retinoic acid(tretinoin), tazarotene, adapalene, a acitretin, 13 cis retinoic acid(isotretinoin), 9 cis retinoic acid (alitretinoin) or betaxorene andtheir metabolic and chemical derivatives. Antimicrobial agents such asmetronidazole, sodium sulfacetamide-sulfur or azaleic acid, α-adrenergicreceptor agonist such as brimonidine, oxymetazoline, naphazoline,tetrahydrozoline, xylometazoline, phenylephrine, methoxamine,mephentermine, metaraminol, midodrine, epinephrine, clonidine ornorepinephrine.

Under such embodiments, at least one of said at least one furtherpharmaceutical active agent and/or said BPO are encapsulated in amicrocapsule.

This invention also features compositions formulated as medicaments forimproving, preventing and/or treating a skin condition, notably rosacea,and which substantially reduce the duration of the treatment and whichprovide a greater reduction of the symptoms of rosacea.

In some embodiments, said benzoyl peroxide is present in the compositionin an amount of at least about 1.0% by weight of said composition.

In some further embodiments, said benzoyl peroxide is present in thecomposition in an amount between about 2.5% to about 10% by weight ofsaid composition. In further embodiments said benzoyl peroxide ispresent in the composition in an amount of between about 2.5% to about5% by weight of said composition.

In further embodiments, said benzoyl peroxide is in a crystalline form.

In some embodiments, said rosacea is papularpostular rosacea (i.e.inflammatory rosacea, see Rapini, Ronald P. et al. (2007). Dermatology:2-Volume Set. St. Louis: Mosby and James, William et al. (2005).Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.).Saunders p. 245).

In other embodiments, said composition of the invention demonstratesadverse events value of no more than about (less than about) 50% upontopical use in the treatment of rosacea. In some embodiments whereinsaid composition demonstrates adverse events values of no more thanabout (less than about) 40%, 30%, 20% upon topical use in the treatmentof rosacea.

The term “adverse events values” refers to average percentage ofsubjects that experience any adverse events associated with thetreatment of rosacea with a composition of the invention (usually on theskin of a subject treated with a composition of the invention). Anon-limiting list of such adverse events includes: irritation, dryness,scaling, purities, burning and stinging.

A composition of the invention was shown to demonstrate a highpercentage of subjects having a 2-grade improvement in the IGA(Investigator General Assessment) and reached a clear or almost clearcondition of the disease, relative to baseline, at week 12.

In some embodiments said 2-grade improvement in the IGA was betweenabout 20% to about 80%, in some other embodiments 30% to 70%, in somefurther embodiments 40-60%.

The term “dissolution rate of BPO from composition” refers to thequantitative amount of BPO dissolved from the composition of theinvention in units of mg of BPO per time (h).

It is to be understood that the inventors of the present applicationhave surprisingly found that a controlled dissolution rate of less thanabout 80% weight/h of BPO from a composition of the invention provides asafe, tolerable and effective treatment of a chronic skin disease suchas rosacea, causing minimal adverse effects upon prolonged use of theskin.

In some further embodiments, a composition of the invention furthercomprises at least one non pharmaceutical active additive selected fromthe group consisting of chelating agents, antioxidants, sunscreens,preservatives, fillers, electrolytes, humectants, dyes, mineral ororganic acids or bases, fragrances, essential oils, moisturizers,vitamins, essential fatty acids, sphingolipids, self-tanning compounds,calmatives and skin-protecting agents, pro-penetrating agents andgelling agents, or a mixture thereof.

In other embodiments, a composition of the invention is formulated intoa topically applicable, physiologically acceptable medium consisting of:(a) at least one member selected from the group consisting of water,alcohols, oils, fatty substances and waxes; and (b) at least oneadditive selected from the group consisting of chelating agents,antioxidants, sunscreens, preservatives, fillers, electrolytes,humectants, dyes, mineral acids, mineral bases, organic acids, organicbases, fragrances, essential oils, moisturizers, vitamins, essentialfatty acids, sphingolipids, self-tanning compounds, calmatives,skin-protecting agents, pro-penetrating agents, gelling agents,emulsifiers, co-emulsifiers, and mixtures thereof.

In some embodiments a composition of the invention is formulated to anemulsion (including an oil-in-water emulsion, a water-in-oil emulsion,multiple emulsions and microemulasions). In other embodiments acomposition of the invention is formulated to a cream. In furtherembodiments, a composition of the invention is formulated to a gel.

The compositions according to the invention are pharmaceuticalcompositions, and especially dermatological compositions, which may bein any galenical form conventionally used for topical application andespecially in the form of aqueous gels, and aqueous or aqueous-alcoholicsolutions. By addition of a fatty or oily phase, it may also be in theform of dispersions of the lotion or serum type, emulsions of liquid orsemi-liquid consistency of the milk type obtained by dispersing a fattyphase in an aqueous phase (0/W) or conversely (W/O), or suspensions oremulsions of soft, semi-liquid or solid consistency of the cream, gel orointment type, or alternatively multiple emulsions (W/O/W or O/W/O),microemulsions, microcapsules, microparticles or vesicular dispersionsof ionic and/or nonionic type, or wax/aqueous phase dispersions. Thesecompositions are formulated according to the usual methods.

In further embodiments, a composition of the invention comprising, as asingle pharmaceutical active agent, benzoyl peroxide in a solid form,for topical use in the treatment of rosacea, is an oil in water emulsioncomprising a polyoxylstearate and a glycerylstearate.

In some embodiments the ratio of said polyoxylstearate to saidglycerylstearate is in the range of 0.1:10 to 10:0.1.

In yet further embodiments, said polyoxylstearate is selected from thegroup consisting of Polyoxyl-8 stearate, Polyoxyl-20 stearate,Polyoxyl-40 stearate, and Polyoxyl-100 stearate.

In further embodiments, said glycerylstearate is selected from the groupconsisting of glyceryl mono-stearate, glyceryl di-stearate and mixturesthereof.

In other embodiments, said polyoxylstearate in said composition is inthe range of about 0.1% w/w to about 30% w/w.

In further embodiments, the amount of said glycerylstearate in saidcomposition is in the range of about 0.1% w/w to about 30% w/w.

In other embodiments, said composition further comprises at least onefatty alcohol.

In other embodiments, said at least one fatty alcohol is selected fromthe group consisting of octyl alcohol, 2-ethyl hexanol, nonyl alcohol,decyl alcohol, undecanol, dodecyl alcohol, tridecyl alcohol, tetradecylalcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol,heptadecyl alcohol, cetostearyl alcohol, stearyl alcohol, isostearylalcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol,elaidolinolenyl alcohol, ricinoleyl alcohol, nonadecyl alcohol,arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol,lignoceryl alcohol, ceryl alcohol, montanyl alcohol, cluytyl alcohol,myricyl alcohol, melissyl alcohol, geddyl alcohol, cetearyl alcohol andmixtures thereof.

In further embodiments, the amount of said at least one fatty alcohol insaid composition is in the range of about 0.2% w/w to about 50% w/w.

In yet other embodiments, said composition further comprises apolyacrylic acid homopolymer or copolymer.

In other embodiments, said oil in said oil in water emulsion is selectedfrom the group consisting of paraffin oil, isopropyl myristate,caprylic/capric triglyceride, squalane, squalene, almond oil, castoroil, olive oil, jojoba oil, sunflower oil, soybean oil, grape seed oil,dimethicone, cyclomethicone and mixtures thereof.

In further embodiments, said oil in present in the composition in anamount in the range of about 0.05% w/w to about 50% w/w.

In some embodiments, said water in said oil in water emulsion furthercomprises at least one water soluble humectant.

In other embodiments, said at least one water soluble humectant isselected from the group consisting of propylene glycol, glycerin, andpolyethylene glycol-X, where X is in the range of 200 to 10,000.

In yet other embodiments, a composition of the invention comprising, asa single pharmaceutical active agent, benzoyl peroxide in a solid form,for topical use in the treatment of rosacea, is in a gel form comprisingat least one non-ionic polymeric dispersant and at least one thickeningagent.

In some embodiments, said at least one non-ionic polymeric dispersant isselected from the group consisting of poly vinyl pyrrolidone (PVP), polyvinyl pyrrolidone-co-vinyl acetate, polyamide, polyurethane, polyureaand mixtures thereof.

In some further embodiments, said at least one thickening agent isselected from the group consisting of hydroxy propyl cellulose (HPC),hydroxyl ethyl cellulose (HEC), hydroxyl methyl cellulose (HMC),polyacrylic acid homopolymer, polyacrylic acid copolymer, fatty alcohol,silica and its derivatives, xanthan gum, arabic gum, poly vinyl alcohol,veegum, laponite, clay, and mixtures thereof.

In other embodiments, said at least one thickening agent is a non-ionicagent.

In further embodiments, said at least one thickening agent is an ionicagent.

In other embodiments, said at least one thickening agent is present inthe composition in an amount in the range of about 0.01% w/w to about10% w/w.

In further embodiments, said composition further comprises glycerin.

In other embodiments, said non-ionic polymeric dispersant is present inthe composition in an amount in the range of about 0.05% w/w to about20% w/w.

In some embodiments, said composition of the invention comprises saidsolid BPO is in a controlled release drug delivery system.

In further embodiments, said controlled or slowed release drug deliverysystem is an encapsulation in a microcapsule, wherein said solid BPO isembedded in said microcapsule.

When referring to a “controlled or slowed release drug delivery system”it should be understood to relate to a delivery system (which in thepresent invention is a topical delivery system) that enables the releaseof the pharmaceutical active agent in predetermined amounts over aspecified period. In some embodiments said system is a core-shell systemof a microcapsule or a porous matrix structure, such as for example amicrosponge.

The term “embedded” should be understood to encompass an inert systemthat provides a barrier between the pharmaceutical active agent, i.e.BPO, and its surrounding environment in the composition. In someembodiments said agent is entrapped and/or encapsulated in saidcontrolled release system.

In some embodiments said core of said microcapsule consists of saidsolid BPO.

In some further embodiments, said microcapsules are a core shellmicrocapsule. The shell comprises at least one inorganic polymer. Insome other embodiments, said inorganic polymer of said shell is a metaloxide or semi-metal oxide shell (layer).

In some embodiments of the invention said microcapsule consists of ametal oxide or semi-metal oxide coating or layer (shell) and a coreconsisting of solid BPO.

In some embodiments said microcapsule consisting of a metal oxide orsemi-metal oxide coating or layer (shell) and a core consisting of solidBPO is prepared by a process comprising the steps of:

-   (a) contacting a solid BPO particulate matter with an ionic additive    and an aqueous medium to obtain a dispersion of said particulate    matter having positive charges on its surface;-   (b) subjecting the particulate matter to a coating procedure    comprising precipitating a metal oxide salt onto the surface of the    particulate matter to form a metal oxide layer thereon thereby to    obtain particulate matter coated by a metal oxide coating layer;-   (c) repeating step (b) at least 4 more times; and-   (d) aging said coating layer.

As used herein the term “solid BPO particulate matter” refers to a solidBPO having solubility in water of less than 1% w/w, typically less than0.5% and at times less than 0.1% w/w at room temperature (20° C.).

The “solid BPO particulate matter” constitutes the “core” of theparticles obtained by the process. The solid BPO particulate matter, is,in some embodiments, in such a state of subdivision that it can besuspended in water, e.g. in the form of a finely-divided powder having aD₉₀ (see definition below), in some embodiments in the range of 0.3-50micron. Such a particulate matter can readily be suspended in an aqueoussystems by stirring, with or without the aid of a surfactant.

The terms “solid BPO particulate matter” and “particulate matter” willbe used interchangeably.

In the present invention the terms “layer”, “coating” or “shell” andsimilar terms, refer to a layer of metal oxide or semi-metal oxideformed around a particle or particulate matter. The layer or coating maynot always be complete or uniform and may not necessarily lead tocomplete coverage of the particulate matter or particle surface. It isappreciated that upon repetition of the coating steps as the coatingprocess proceeds a more uniform coating and more complete coverage ofthe particulate matter is obtained.

The term “dispersion” as used herein in step (a) of the process refersto a solid dispersion of the particulate matter in the aqueous medium.

Step (a) of the process may further comprise reducing the particle sizeof the particulate matter to the desired particle size for example bymilling or homogenization.

The core (i.e. solid, BPO particulate matter) may be of any shape forexample rod-like, plate-like, ellipsoidal, cubic, or spherical shape.

Referring to size of particles will be through their D₉₀ meaning that90% of the particles have the stated dimension or less (measured byvolume). Thus, for examples, for spherical particles stated to have adiameter of 10 micrometer (“microns”), this means that the particleshave a D₉₀ of 10 microns. The D₉₀ may be measured by laser diffraction.For particles having a shape other than spheres, the D₉₀ refers to themean average of the diameter of a plurality of particles.

In the case of cores having a spherical shape, the diameter (D₉₀) may bein the range of 0.3 to 90 microns, in some embodiments 0.3 to 50microns, in some other embodiments 1 to 50, in some further embodiments5 to 30 microns.

By the term “D₉₀ may be in the range of 0.3 to 90 microns” is meant that90% by volume of the particles (in this case the particle's core) may beless than or equal to a value in the range of 0.3 to 90 microns.

For generally cubic-shaped cores or cores having a shape resembling thatof a cube, the mean size of a side may be in the range 0.3 to 80microns, in some embodiments 0.3 to 40 microns, in some furtherembodiments 0.8 to 40, in some further embodiments 4 to 15 microns.

For rod-like shaped, ellipsoidal-shaped and plate-like shaped cores, thelargest dimension (that of the longest axis) is typically in the range10 to 100 microns, in some embodiments 15 to 50 microns; and thesmallest dimension is typically in the range 0.5 to 20 microns, in somefurther embodiments 2 to 10 microns.

As used herein, unless otherwise indicated, the term “particle” refersto the metal oxide or semi-metal oxide coated particulate matter.

It is appreciated that some of the particles obtained by the process mayat times be formed from two or more original particles of the solid BPOparticulate and may accordingly include at times more than one core,such cores being separated from each other by a metal oxide region.

The weight of the solid BPO particulate (core material) based on thetotal weight of the particle may be in the range 99%-50% w/w, in someembodiments in the range 97%-50% w/w. The core material may be in acrystalline form, amorphous form, or combination thereof. The corematerial may be a cosmetically, pharmaceutically or an agrochemicalactive ingredient.

In some embodiments, step (c) of the process described above is repeated4 to about 1000 times. This means that in some embodiments step (b) ofthe process described above is repeated 4 to about 1000 times.

In further embodiments, the process comprising repeating step (c) 4 toabout 300 times, and in some further embodiments 4 to about 100 times.In some other embodiments step (c) of the process described above isrepeated 5-80 times in some embodiments 5-50 times. This means that insome embodiments step (b) is repeated as indicated above with respect tostep (c).

By the term “repeated 4 to about 1000 times” is meant that the processmay be repeated 4, 5, 6, 7, 8, 9 . . . , etc. times up to and includingabout 1000 times.

According to some embodiments of the present invention step (d) furthercomprising after aging, separating the coated particulate matter fromthe dispersing aqueous medium, such as by filtration, centrifugation ordecantation and optionally rinsing and re-dispersing the obtained coatedparticulate matter in an aqueous medium.

In some embodiments, during the coating process at least 50% of thecontent the particulate matter (pharmaceutical active agent) in theaqueous medium is in a solid state during the coating process.

According to some embodiments of the present invention the processcomprising:

-   (a) contacting the solid, BPO particulate matter, with a first    cationic additive and an aqueous medium to obtain a dispersion of    said particulate matter having positive charges on its surface;-   (b) subjecting the particulate matter to a coating procedure    comprising precipitating a metal oxide salt onto the surface of the    particulate matter to form a metal oxide coating layer on the    particulate matter;-   (b1) in an aqueous medium, contacting the coated particulate matter    with a surface adhering additive being one or both of (i) a second    cationic additive, and (ii) a non-ionic additive;-   (b2) subjecting the particulate matter obtained in step (b 1) to a    coating procedure as in step (b);-   (c) repeating steps (b1) and (b2) at least 3 more times; and-   (d) aging the metal oxide coating layer.

In some embodiments, the process comprising repeating step (c) 3 toabout 1000 times.

In some other embodiments, the process comprising repeating step (c) 3to about 300 times, and in yet further embodiments 3 to about 100 times.

As used herein by the term “repeating step (c) 3 to about 1000 times” ismeant that the process may be repeated 3, 4, 5, 6, 7, 8, 9, . . . etc.times up to and including about 1000 times.

This means that in some embodiments steps (b1) and (b2) are repeated asindicted above with respect to step (c).

Additionally according to some embodiments of the present invention theprocess comprising:

-   (a) contacting the solid, BPO particulate matter, with an anionic    additive, a first cationic additive and an aqueous medium to obtain    a dispersion of said particulate matter having positive charges on    its surface;-   (b) subjecting the particulate matter to a coating procedure    comprising precipitating a metal oxide salt onto the surface of the    particulate matter to form a metal oxide coating layer on the    particulate matter;-   (b1) in an aqueous medium, contacting the coated particulate matter    with a surface adhering additive being one or both of (i) a second    cationic additive, and (ii) a non-ionic additive;-   (b2) subjecting the particulate matter obtained in step (b1) to a    coating procedure as in step (b);-   (c) repeating steps (b1) and (b2) at least 3 more times; and-   (d) aging the metal oxide coating layer.

When an anionic additive and first cationic additive are used in step(a) of the process, in some embodiments the anionic additive is addedbefore the first cationic additive.

Step (c) may be repeated 3 to about 1000 times. In some embodiments,step (c) is repeated 3 to about 300 times, in some other embodiments, 3to about 100 times. This means that in some embodiments steps (b1) and(b2) are repeated as indicted above with respect to step (c).

The ionic additive (such as first cationic additive) used in step (a) ofthe process have a dual effect: to form positive charges on the surfaceof the particulate matter as will be described below, and also to serveas a wetting agent, thus allowing dispersion of the particulate matteras discrete core particles, where each core particle is individuallysuspended in the aqueous medium.

Step (a) of the process may be conducted for example by (i) contactingthe particulate matter with dry ionic additives and then suspending bothin an aqueous medium to obtain a dispersion of said particulate matterhaving positive charges on its surface, or alternatively by (ii)suspending the solid BPO particulate in an aqueous medium comprisingionic additives to obtain a dispersion of said particulate matter havingpositive charges on its surface.

According to another embodiment the process may comprise (a) contactingthe solid, BPO particulate matter, with an ionic additive selected from(i) an anionic additive; (ii) a first cationic additive, and acombination thereof, and an aqueous medium to obtain a dispersion ofsaid particulate matter having positive charges on its surface; (b),(b1), (b2), (c), (d) are as described herein.

The concentration of the ionic additives in the dispersion can be about0.001% to about 30%, in some embodiments about 0.01% to about 10% w/wand in some other embodiments about 0.1% up to about 5% w/w.

The solid content of the water dispersion can be about 0.1% to about 80%w/w, in some embodiments about 1% to about 60% w/w, in some furtherembodiments about 3% to about 50% w/w.

The purpose of step (a) is to modify the electrical charge of theparticulate matter by using ionic additives such that it will be madereactive to the attachment of the metal oxide layer. For preparing thecore material of the particles, the particulate matter ought to besuitably coated with an ionic additive (e.g. cationic additive), suchthat it can be attached to the precipitated metal oxide salt.

In some embodiments, the ionic additive is selected from a cationicadditive, an anionic additive, and a combination thereof. The cationicadditive may be a cationic surfactant and/or cationic polymer. Theanionic additive may be an anionic surfactant and/or anionic polymer.

The particulate matter is contacted with an ionic additive, for exampleby mixing it with a solution of a cationic surfactant and/or cationicpolymer or an anionic surfactant and a cationic additive (e.g. cationicsurfactant and/or cationic polymer). Cationic and anionic surfactantsare particularly effective in being adsorbed upon the surface of theparticulate matter. The ionic additive may also be anionic polymers usedin combination with a cationic additive. The cationic surfactant and/orthe cationic polymer and optionally further the anionic surfactant (oranionic polymer) need to be used in sufficient amount to providepositive charges on the surface of the particulate matter. The coatingneed not be continues. It is sufficient that there are at least spots ofcationic additive. These spots will then serve as anchors for theattachment of the metal oxide layer. In some embodiments, there areuniform distribution of these anchoring points on the core surface sothat as the metal oxide layer builds up it will bridge over and befirmly attached to the core.

According to some embodiments said first and said second cationicadditive are the same.

According to another embodiment said first and said second cationicadditive are different.

In some other embodiments, the first ionic additive is an anionicsurfactant and the second ionic additive is a cationic polymer. In somefurther embodiments the first cationic additive is a cationic surfactantand the second cationic additive is a cationic polymer.

According to further embodiments, the first cationic additive is acationic surfactant and the additive in step (b1) is a non-ionicadditive (e.g. a non-ionic polymer).

In some further embodiments, the coated particulate matter and thesecond cationic additive are mixed, and most preferable said mixing isunder vigorous stirring (e.g. mixer speed above 1000 rpm).

According to a preferred embodiment of the present invention the processfurther comprising following step (d): (e) separating the coatedparticulate matter from the aqueous medium and optionally rinsing andre-dispersing the coated particulate matter in an aqueous medium.

In some embodiments, the separation of the coated particulate matter isconducted by a method such as filtration, centrifugation, decantation,dialysis, or by evaporation of the aqueous medium.

Additionally according to a preferred embodiment of the presentinvention, step (b) comprises adding a metal oxide salt to the aqueousmedium; and optionally acidifying the aqueous medium.

Further according to some embodiments of the present invention, step(b2) comprises adding a metal oxide salt to the aqueous medium; andoptionally acidifying the aqueous medium.

In some embodiments step (b1) further comprising adjusting the pH of thedispersion obtained in (b) to a value higher than the isoelectric pointof the metal oxide before adding the second cationic additive, in somefurther embodiments to a pH value of at least about 1 unit higher thanthe isoelectric point of the metal oxide, before adding the secondcationic additive.

In some embodiments, step (b1) further comprising adjusting the pH ofthe dispersion obtained in (b) to a value higher than the isoelectricpoint of the metal oxide before adding one or both of (i) a secondcationic additive, and (ii) a non-ionic additive, in some embodiments toa pH value of at least about 1 unit higher than the isoelectric point ofthe metal oxide, before adding one or both of (i) a second cationicadditive, and (ii) a non-ionic additive.

For example, in case the metal oxide is silica (e.g. having anisoelectric point in the range 1.7-2.5) the preferred pH may be at leastin the range of about 2.5-6.5.

The purpose of the pH adjustment of the dispersion to a value higherthan the isoelectric point of the metal oxide is to form negativelycharged metal oxide on the particulate matter surface that will be boundto the positive charges of the second cationic additive thus enablingthe attachment of the second cationic additive to the surface of theparticulate matter.

The non-ionic additive is of a kind that adheres to the surface(“surface-adherent”). An example is a non-ionic polymer. The non-ionicadditive may be used alone or in addition to the second cationicsurfactant. Without wishing to be bound by theory, the surface-adherentproperty may be through hydrogen-binding groups such as hydroxyl oramine groups. This allows adhesion of a further layer of metal oxide onthe preceding precipitated metal oxide layer.

In some embodiments, the particulate matter/metal oxide salt weightratio, in each of the steps (b) or (b2) is about 5,000/1 to about 20/1,in some embodiments about 5,000/1 to about 30/1, or about 5,000/1 toabout 40/1, in some further embodiments about 1,000/1 to about 40/1, andin yet some further embodiments about 500/1 to about 80/1.

In some embodiments, the particulate matter/cationic additive ratio, instep (b 1) is about 25,000/1 to about 50/1, preferably about 5,000/1 toabout 100/1, and most preferably about 2000/1 to about 200/1.

According to some embodiments the particulate matter/metal oxide saltweight ratio, in each of the steps (b) or (b2) is about 5,000/1 to about65/1, and in some further embodiments about 1000/1 to about 100/1.

In some embodiments, the particulate matter/cationic additive weightratio, in step (b1) is about 10,000/1 to about 100/1, and in somefurther embodiments about 5000/1 to about 200/1.

The aging in step (d) is crucial for obtaining a strengthened and denselayer of metal oxide.

In some embodiments step (d) comprises raising the pH to a value in therange 3-9 and mixing the suspension in this pH.

According to a preferred embodiment of the present invention step (d)comprises raising the pH to a value in the range 3-9 and mixing thesuspension in this pH for a period of at least 2 h.

According to some embodiments of the present invention step (d)comprises raising the pH to a value in the range 3-9, in some furtherembodiments to a range of 5-7, and mixing, e.g. by stirring, thesuspension (dispersion) in this pH range e.g. for a period of at least 2h (two hours). In some embodiments, stirring is for 2-96 h, in someembodiments 2-72 h, in some other embodiments at least 10 h (for example10-72 h). In some embodiments the stirring is a gentle stirring, in someembodiments in the range 200-500 rpm.

Upon completion of aging, the separation (e.g. filtration,centrifugation or decantation) will be easy to perform (due to the hardmetal oxide layer formed) and the obtained cake or concentrateddispersion will be easily re-dispersed in an aqueous medium to form adispersion of particles.

The purpose of aging in step (d) is to obtain a strengthened and denserlayer of metal oxide.

In the absence of the aging step a thinner and softer layer of metaloxide would be obtained since the metal oxide salt upon precipitationforms a gel layer of metal oxide which may disintegrate or erode uponseparation and washing or by mechanical stirring.

The aging may be conducted at a temp of 4-90° C., in some embodiments at15-60° C. and in further embodiments the aging is conducted at atemperature 20° C.-40° C.

Thus the repeated steps of coating and aging at the end of the processalso enable the growth of thicker and stronger layer of metal oxide. Insome embodiments aging is not conducted between the repeated coatingsteps (i.e. between the repeated coating step (b)), but only at the endof the process. Thus in some embodiments the aging is conducted only atthe end of the process described herein.

According to certain embodiments, the process may further compriseadding a colloidal metal oxide suspension, in some embodimentsaqueous-based suspension (comprising nanometric metal oxide(nanoparticles of metal oxide) during the coating procedure. In someembodiments the colloidal metal oxide suspension is selected fromcolloidal silica suspension, colloidal titania suspension, colloidalalumina suspension, colloidal zirconia suspension, colloidal ZnOsuspension, and mixtures thereof. The colloidal metal oxide suspensionmay be added during the coating process (e.g. in step (b) in one or moreof its repeated steps). In some other embodiments the size of thenanometric metal oxide in diameter is in the range between 5-100 nm(average particle size diameter). The weight ratio of the nanometricmetal oxide to the metal oxide salt may be in the range 95:5 to 1:99 insome embodiments 80:20 to 5:95 in some other embodiments 70:30 to 10:90,in yet other embodiments about 60:40 to 20:80. The weight ratio of thenanometric metal oxide to the metal oxide salt may be about 50:50.

According to other embodiments, the process does not include addition ofcolloidal metal oxide suspension during the coating process. Accordingto this embodiment nanometric metal oxide particles (nanoparticles ofmetal oxide) are not added during the coating process.

As used herein, the term “metal oxide coating layer” or “metal oxidelayer” encompasses the product of both a single processing step as wellas a product of the process in which the initially coated particles arefurther processed, by the repeated processing steps of step (c),described above.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the disclosure and to see how it may be carriedout in practice, embodiments will now be described, by way ofnon-limiting example only, with reference to the accompanying drawings,in which:

FIG. 1 is a graph presenting the mean IGA per time of BPO composition ofthe invention (1% and 5% encapsulated BPO as described in example 1) ascompared with vehicle alone over a period of time of 12 weeks.

FIG. 2 is a graph presenting the is the mean inflammatory lesion countper time of BPO composition of the invention (1% and 5% encapsulated BPOas described in example 1) as compared with vehicle alone over a periodof time of 12 weeks.

FIG. 3 is a graph presenting the dissolution rate of BPO over a periodof 60 minutes of a composition of the invention (5% E-BPO, producedaccording to Example #3), and Benzac® AC 5% BPO and NeoBenz® Micro 5.5%.

DETAILED DESCRIPTION OF EMBODIMENTS Example 1: Encapsulation of BPO

Step 1: Milling:

110 g. of hydrous BPO 75% (USP grade from Sigma) were suspended in 152g. of 0.4% CTAC solution containing 0.001% silicon antifoam. The BPO wasmilled using a stator rotor mixer (Kinematika polytron 6100 operated at15,000 rpm/25 m/s). The milling was stopped when the particle sizedistribution (PSD) of the suspension was d(0.9)<35 μm or the temperaturehas reached 50 C. The final suspension was cooled to room temperature.

Step 2a: Coating Option #1:

During the coating procedure the suspension was stirred with amechanical dissolver, 80 mm, at 500 RPM at all times. The pH of themilled BPO suspension was corrected to 8 using NaOH 5N solution. Aportion of 1 g of 15% sodium silicate solution (15% w/w as SiO₂) wasadded and the suspension was stirred for 5 min. A portion of 1 g of 3%Polyquaternium 7 was added and the suspension was stirred for 5 min. pHwas adjusted to 6-7 using 5N HCl solution.

This procedure was repeated for 5-100 times in order to create a seriesof silica layers around BPO having different thickness.

Step 2b: Coating Option #2:

During the coating procedure the suspension was stirred with amechanical dissolver, 80 mm, at 500 RPM at all times. The pH of themilled BPO suspension was corrected to 8 using NaOH 5N solution. Aportion of 2.5 g of 15% sodium silicate solution (15% w/w as SiO₂) wasadded and the suspension was stirred for 5 min. A portion of 2.5 g of 3%Polyquaternium 7 was added and the suspension was stirred for 5 min. pHwas adjusted to 6-7 using 5N HCl solution.

This procedure was repeated for 5-100 times in order to create a seriesof silica layers around BPO having different thickness.

The Aging Step:

The coated BPO suspension at pH 6.5 was kept for aging at roomtemperature (25 C+/−2) under gentle agitation for 24 hrs.

Example 2: Preparation of Encapsulated BPO (15% E-BPO Water Suspension)

a) Preparation of Benzoyl Peroxide Dispersion and Acid Cocktail

A benzoyl peroxide (BPO) dispersion was prepared by mixing 125.67 gramsof CTAC CT-429 (Cetrimonium Chloride 30%), 3008 grams of hydrous benzoylperoxide, and 5200 grams water under high shear. The dispersion washomogenized for 60 minutes at 33° C. (no more than 45° C.), and then thepH of the dispersion was adjusted to 7.0 using sodium hydroxide solution(20%).

An acid cocktail was prepared using 493 grams Hydrochloric acid (37%),98 grams anhydrous Citric Acid, 147 grams Lactic Acid (90%), and 794grams water.

b) Coating Cycle

The coating cycle was started by adding 38 grams sodium silicatesolution extra pure (28%) to the benzoyl peroxide dispersion prepared instep a) under high shear, followed by adding the acid cocktail preparedin step (a) to adjust the pH to be lower than 6.8, and followed byadding 57 grams PDAC (3%) solution to the mixture. The cycle wasrepeated 50 times while the mixture was stirred under high shear for 17hours. After the 50 cycles, the pH of the mixture was adjusted to 5.0using the acid cocktail, and water was added to complete the totalweight of the mixture to 15 kilograms. The composition of the final BPOwater suspension product is shown in Table 1.

TABLE 1 Composition of the encapsulated BPO 15% water suspensionIngredient % of ingredient in the suspension Polyquarternium-7 0.53Hydrochloric Acid 0.87 Citric Acid, Anhydrous 0.46 Lactic Acid 0.63Silicon Dioxide 3.42 Sodium hydroxide 0.01 Cetrimonium Chloride 0.25Hydrous Benzoyl Peroxide 15.00 Sterile Water for Irrigation Up to 100%

Example 3: Preparation of Formulation of Encapsulated BPO (5%) Gel(Formulation I)

Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams CetylAlcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams of GlycerylMonosterate were mixed at 70° C. Water phase: 18.0 grams ofEthylendiaminetetraacetate Disodium salt were dissolved in 6500 grams ofwater. 720.0 grams of glycerin (99.5%) were added to the solution. Afterthe solution was heated to 70° C., 72.0 grams of Carbopol 980 NF wereadded and the resulting mixture was homogenized at 3300 rpm for 10minutes to ensure that all materials completely melted and dissolved.76.5 grams if sodium hydroxide (20%) were then added and the mixture wasstirred under high shear for 10 minutes at no less than 70° C.

The oil phase was added to the water phase under high shear at 78° C.,and the resulting emulsion was homogenized at 3300 rpm for 10 minutes.72.0 grams of Citric Acid and 6,000 grams of encapsulated BPO 15% watersuspension made as described in Example 2 were mixed. The resultingmixture was added to the emulsion at 65° C. and mixed at 1400 rpm for 10minutes. The emulsion was cooled to 35° C. and the pH of the emulsionwas adjusted to 4.0 using HCl 5N solution. The emulsion was stirred at1400 rpm for 10 minutes and then water was added until the total weightof the emulsion reached 18 kilograms. The composition of the formulationprepared in this example is shown in Table 2.

TABLE 2 Composition of Formulation I Ingredient % of pure ingredient inthe composition Polyquarternium-7 0.17 Hydrochloric Acid 0.37 CitricAcid, Anhydrous 0.38 Lactic Acid 0.21 Silicon Dioxide 1.14 Sodiumhydroxide 0.08 Cetrimonium Chloride 0.1 Hydrous Benzoyl Peroxide 5.00Glycerin 4.00 Polyoxyl 100 stearate 2.00 Cetyl alcohol 3.00Cyclomethicone 4.00 Glyceryl monostearate 3.00 Edetate Disodium 0.10Carbopol 980 0.40 Sterile Water for Irrigation up to 100%

Example 4: Preparation of Placebo of Encapsulated BPO Water Suspension

-   -   a) Preparation of Placebo Dispersion and Acid Cocktail

A placebo dispersion was prepared by mixing 125.67 grams of CTAC CT-429(Cetrimonium Chloride 30%), and 5200 grams and then the pH of thesolution was adjusted to 7.0 using sodium hydroxide solution (20%).

An acid cocktail was prepared using 493 grams Hydrochloric acid (37%),98 grams anhydrous Citric Acid, 147 grams Lactic Acid (90%), and 794grams water.

b) Coating Cycle

The coating cycle was started by adding 38 grams sodium silicatesolution extra pure (28%) to the placebo solution prepared in step a)under high shear, followed by adding the acid cocktail prepared in step(a) to adjust the pH to be lower than 6.8, and followed by adding 57grams PDAC (3%) solution to the mixture. The cycle was repeated 50 timeswhile the mixture was stirred under high shear for 17 hours. After the50 cycles, the pH of the mixture was adjusted to 5.0 using the acidcocktail, and water was added to complete the total weight of themixture to 15 kilograms. The composition of the final placebo watersuspension product is shown in Table 3.

TABLE 3 Composition of placebo of encapsulated BPO water suspensionIngredient % of ingredient in the suspension Polyquarternium-7 0.53Hydrochloric Acid 0.87 Citric Acid, Anhydrous 0.46 Lactic Acid 0.63Silicon Dioxide 3.42 Sodium hydroxide 0.01 Cetrimonium Chloride 0.25Sterile Water for Irrigation Up to 100%

Example 5: Preparation of Formulation of Vehicle of Encapsulated BPO Gel(Formulation II)

Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams CetylAlcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams of GlycerylMonosterate were mixed at 70° C.

Water phase: 18.0 grams of Ethylendiaminetetraacetate Disodium salt weredissolved in 6500 grams of water. 720.0 grams of glycerin (99.5%) wereadded to the solution. After the solution was heated to 70° C., 72.0grams of Carbopol 980 NF were added and the resulting mixture washomogenized at 3300 rpm for 10 minutes to ensure that all materialscompletely melted and dissolved. 76.5 grams if sodium hydroxide (20%)were then added and the mixture was stirred under high shear for 10minutes at no less than 70° C.

The oil phase was added to the water phase under high shear at 78° C.,and the resulting emulsion was homogenized at 3300 rpm for 10 minutes.72.0 grams of Citric Acid and 6,000 grams of placebo of encapsulated BPOwater suspension made as described in Example 4 were mixed.

The resulting mixture was added to the emulsion at 65° C. and mixed at1400 rpm for 10 minutes. The emulsion was cooled to 35° C. and the pH ofthe emulsion was adjusted to 4.0 using HCl 5N solution. The emulsion wasstirred at 1400 rpm for 10 minutes and then water was added until thetotal weight of the emulsion reached 18 kilograms. The composition ofthe formulation prepared in this example is shown in Table 4.

TABLE 4 Composition of Formulation II Ingredient % of pure ingredient inthe composition Polyquarternium-7 0.17 Hydrochloric Acid 0.37 CitricAcid, Anhydrous 0.38 Lactic Acid 0.21 Silicon Dioxide 1.14 Sodiumhydroxide 0.08 Cetrimonium Chloride 0.1 Glycerin 4.00 Polyoxyl 100stearate 2.00 Cetyl alcohol 3.00 Cyclomethicone 4.00 Glycerylmonostearate 3.00 Edetate Disodium 0.10 Carbopol 980 0.40 Sterile Waterfor Irrigation up to 100%

Example 6: Preparation of Formulation of Encapsulated BPO (1%) Gel(Formulation III)

Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams CetylAlcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams of GlycerylMonosterate were mixed at 70° C.

Water phase: 18.0 grams of Ethylendiaminetetraacetate Disodium salt weredissolved in 6500 grams of water. 720.0 grams of glycerin (99.5%) wereadded to the solution. After the solution was heated to 70° C., 72.0grams of Carbopol 980 NF were added and the resulting mixture washomogenized at 3300 rpm for 10 minutes to ensure that all materialscompletely melted and dissolved. 76.5 grams if sodium hydroxide (20%)were then added and the mixture was stirred under high shear for 10minutes at no less than 70° C.

The oil phase was added to the water phase under high shear at 78° C.,and the resulting emulsion was homogenized at 3300 rpm for 10 minutes.72.0 grams of Citric Acid, 1200 grams of encapsulated BPO 15% watersuspension made as described in Example 2 and 4800 grams of placebo ofencapsulated BPO water suspension as described in Example 4 were mixed.The resulting mixture was added to the emulsion at 65° C. and mixed at1400 rpm for 10 minutes. The emulsion was cooled to 35° C. and the pH ofthe emulsion was adjusted to 4.0 using HCl 5N solution. The emulsion wasstirred at 1400 rpm for 10 minutes and then water was added until thetotal weight of the emulsion reached 18 kilograms. The composition ofthe formulation prepared in this example is shown in Table 5.

TABLE 5 Composition of Formulation III Ingredient % of pure ingredientin the composition Polyquarternium-7 0.17 Hydrochloric Acid 0.37 CitricAcid, Anhydrous 0.38 Lactic Acid 0.21 Silicon Dioxide 1.14 Sodiumhydroxide 0.08 Cetrimonium Chloride 0.1 Hydrous Benzoyl Peroxide 1.00Glycerin 4.00 Polyoxyl 100 stearate 2.00 Cetyl alcohol 3.00Cyclomethicone 4.00 Glyceryl monostearate 3.00 Edetate Disodium 0.10Carbopol 980 0.40 Sterile Water for Irrigation up to 100%

Example 7: Efficacy Study of BPO in a Composition of the Invention

A multi-center, double-blind, randomized, vehicle-controlled, dose-rangestudy was performed. Study duration was 12 weeks on mild to severefacial rosacea patients using encapsulated benzoyl peroxide gel, 1% (asdescribed in Example 6) and 5% (as described in Example 3), and vehiclegel (as described in Example 5) once daily.

A total of 92 subjects were randomly assigned in a 1:1:1 ratio to 5%E-BPO Gel, 1% E BPO Gel, or Vehicle Gel.

The investigator performed the Investigator Global Assessment (IGA) andinflammatory lesion (papules and pustules) counts at Screening,Baseline, and Weeks 4, 8, and 12 (end of study).

Evaluation of Efficacy:

The first application of the test product was applied at theinvestigational site at the end of the Baseline visit (Day 0) under thesupervision and instruction of the designated investigational sitestaff. The investigator performed the Investigator Global Assessment(IGA) and inflammatory lesion (papules and pustules) counts atScreening, Baseline, and Weeks 4, 8, and 12 (end of study) and erythemaand telangiectasia assessments at Baseline, and Weeks 4, 8, and 12 (endof study). The evaluator also assessed local application site irritation(dryness, scaling, pruritus, stinging and burning) at Baseline and Weeks2, 4, 8 and 12 (end of study). At selected investigational site(s),standardized photography of facial rosacea also was performed atBaseline and Week 8 and 12 (end of study). Information on adverse events(AEs) was collected at all visits.

Efficacy endpoints were: Proportion of subjects with the primary measureof success, defined as a 2-grade improvement in the IGA relative toBaseline at Week 12, with the Week 12 IGA of clear or almost clear.Change in inflammatory lesion count at Week 12.

Results:

Baseline Characteristics: The Baseline characteristics were similaramong the treatment groups for IGA and telangiectasia. While the medianinflammatory lesion counts were similar among the treatment groups, themean inflammatory lesion count was numerically higher for 1% E-BPO Gelthan for 5% E-BPO Gel and for 1% E-BPO Gel and 5% E-BPO Gel than forVehicle Gel, and a numerically higher proportion of subjects in 1% E-BPOGel than in 5% E-BPO Gel and 1% E-BPO Gel and 5% E-BPO Gel than inVehicle Gel had severe inflammatory lesion erythema at Baseline. Anumerically higher proportion of subjects in 1% E-BPO Gel and 5% E-BPOGel than in Vehicle Gel had severe rosacea erythema

Primary Efficacy Analyses

For the Primary Efficacy Endpoints:

The proportions of subjects with the primary measure of success (definedas a 2-grade improvement in the IGA relative to Baseline at Week 12,with the Week 12 IGA of clear or almost clear) were 20.0% (6/30) forVehicle Gel, 37.5% (12/32) for 1% E-BPO Gel, and 53.3% (16/30) for 5%E-BPO Gel. The improvement in mean IGA is described in FIG. 1.

The proportions of subjects with the 2^(nd) primary measure of success(defined as mean inflammatory lesion count percent change from Baselineat Week 12) were about 30.0% for Vehicle Gel and more than 60% for 1%E-BPO Gel and 5% E-BPO Gel

The improvement in inflammatory lesion count is described in FIG. 2.

Example 8: Measuring the Dissolution Rate of BPO from a Composition ofthe Invention

Weighing of Samples

A sample was weighed according to its BPO content in amount equivalentto 40 mg of BPO. Examples for weight of samples are given in the tablebelow.

Concentration of BPO in the sample (C₀) 1% (w/w) 5% (w/w) 10% (w/w)Weight of sample, mg 3200-4800 640-960 320-480

Preparation of Samples and Measurement Procedure

The sample was weighed into a 250 mL Erlenmeyer flask, 200 mL of“medium” were added and a 3.0 cm length magnetic bar was inserted, theflask was placed on the stirrer and stirring at 400 rpm was started. 2mL at specified time intervals were withdrawn and filtered through 0.2μm GHP Acrodisc syringe filter (first mL discarded). The concentrationof BPO (in % w/w) dissolved in each time interval (C_(n)) werecalculated.

The “medium” was prepared by mixing 550 mL of water with 450 mL ofacetonitrile, which were than equilibrated to ambient temperature.

The dissolution rate was measured according to the following formula:

The dissolution rate (%)=(C _(n) /C ₀)*100%

Dissolution Rate of BPO in Compositions of the Invention

The dissolution rate of a composition of the invention comprising 5%E-BPO, produced according to Example #3, were compared with thedissolution of Benzac® AC 5% BPO and NeoBenz® Micro 5.5%. As can be seenfrom the results presented in FIG. 3, the dissolution rate of acomposition of the invention was much lower than the dissolution of theabove commercial products.

What is claimed is:
 1. A composition for the topical treatment of rosacea, comprising as a sole pharmaceutical active agent benzoyl peroxide in solid form, wherein the composition comprises 5% by weight of said benzoyl peroxide and said composition is an oil-in-water emulsion; wherein said solid benzoyl peroxide is encapsulated as the core of a microcapsule having a shell comprising between 5-100 layers of metal oxide, and wherein said composition has a dissolution rate of less than 80% weight/h as measured in a medium of 55%:45% mixture of water and acetonitrile at ambient temperature.
 2. The composition of claim 1, wherein said benzoyl peroxide has a dissolution rate of less than about 60% weight/h. 